Meals terminate when the majority of ingested nutrients are still in the gastrointestinal tract and not yet available for energy metabolism. Although a variety of preabsorptive feedback signals arising from various sites in the GI tract have been identified, an assessment of their quantitative contribution to feeding control requires a consideration of the overall context in which these signals are produced. During feeding, multiple gastrointestinal sites are stimulated, provoking a variety of signals related to nutrient character, concentration and quantity. These nutrient stimulated signals exert major negative feedback influences on ongoing food intake. Food intake is also affected by the activity of hypothalamic signaling systems involved in overall energy balance. The discovery of leptin, the protein product of the ob gene, has produced significant advances in our understanding of the organization of hypothalamic systems involved in energy regulation. One way in which these hypothalamic signaling systems may exert their effects on food intake is by modulating responsivity to within meal satiety signals to reduce meal size. The proposed experiments will address different aspects of the integration of signals involved in the control of food intake in different models and with diverse experimental approaches. The proposed experiments are organized under two specific aims. Under the first, we will examine the actions of leptin and its down stream mediators in modulating neural and behavioral response to within meal satiety signaling. We will begin with assessments of where and how hypothalamic signaling peptides affect meal patterns. For actions that reduce meal size, we will evaluate the ability of these signals to modulate nucleus of the solitary tract (NTS) responses to within meal feedback signaling. These experiments will employ both c-fos and electrophysiological assessments of NTS neural activation. Finally, these experiments will use electrophysiological techniques to evaluate peptide candidates for hypothalamic-NTS signaling. Experiments under the second specific aim will focus on quantifying peptide secretion from the gastrointestinal tract in response to nutrient exposure. These experiments will employ both primate and rat models. The traditional focus for GI feedback signaling has been on peptides from the upper intestine. Recent data has suggested roles for gastric (ghrelin) and lower intestinal peptides (PYY (3-36) and GLP-1 in feeding control). Patterns of peptide release in response to site directed nutrient delivery have not been completely characterized. An understanding of the context within which these peptides are secreted will allow informed assessments of the relative contributions to both within meal and across meal feeding control. These latter data will have implications for understanding the feeding and weight loss effects of bariatric surgery. Overall, these experiments will provide important information on the relative roles and integrative actions of peptide systems involved in feeding control.